A number of symptomologies which result in cognitive deficits, stroke, brain hemorrhage, and general mental debilitation appear to be associated with neuritic and cerebrovascular plaques in the brain containing the amyloid beta peptide (Aβ). Among these conditions are both preclinical and clinical Alzheimer's disease, Down's syndrome, and preclinical and clinical cerebral amyloid angiopathy (CAA). The amyloid plaques are formed from amyloid beta peptides. These peptides circulate in the blood and in the cerebrospinal fluid (CSF). The Aβ peptide in circulating form is composed of 39-43 amino acids (mostly 40 or 42 amino acids) resulting from the cleavage of a common precursor protein, amyloid precursor protein, often designated APP.
Evidence suggests that Aβ can be transported back and forth between brain and the blood (Ghersi-Egea, J-F., et al., J. Neurochem. (1996) 67:880-883; Zlokovic, B. V., et al., Biochem. Biophys. Res. Comm. (1993) 67:1034-1040; Shibata, M., et al., J. Clin. Invest. (2000)106:1489-1499. Further Aβ in plaques is in an equilibrium with soluble Aβ in the brain and blood (Kawarabayashi, T., et al., J. Neurosci. (2001) 21:372-381), DeMattos et al., Proc. Nat'l. Acad. Sci USA (2001) 98:8850-8855.
As described in PCT application US00/35681 and U.S. Ser. No. 09/153,130 both incorporated herein by reference, total circulating levels of Aβ peptide in CSF are similar in normal individuals and individuals predisposed to exhibit the symptoms of Alzheimer's. However, Aβ42 levels are lower on average in individuals with Alzheimer's disease (Nitsch, R. M., et al., Ann. Neurol. (1995) 37:512-518). It is known that Aβ42 is more prone to aggregate than is Aβ42, and when this happens, adverse consequences such as Aβ deposition in amyloid plaques, conversion of Aβ to toxic forms, nerve cell damage, and behavioral impairment such as dementia ensue (Golde, T. E., et al., Biochem. Biophys. Acta. (2000) 1502:172-187).
PCT application PCT/US01/06191 entitled “Humanized Antibodies That Sequester Aβ Peptide” filed 26 Feb. 2001 and incorporated herein by reference describes antibodies which do not appreciably cross the blood-brain barrier and which sequester Aβ peptides circulating in biological fluids. These antibodies are described as useful for preventive and therapeutic treatment of conditions associated with the formation of Aβ-containing diffuse, neuritic, and cerebrovascular plaques in the brain. The application describes administering the antibodies and then measuring circulating levels of Aβ peptide in blood in order to assess the progress of therapy. There is no clear suggestion, however, that the levels of Aβ peptide following administration of the antibodies are diagnostic of the condition itself. The present invention resides in the surprising result that enhanced levels of both Aβ40 and Aβ42 as well as the Aβ40/Aβ42 ratio correlate with the levels of Aβ peptide deposition in the brain when the antibodies are administered to an individual. Thus, measurement of these components in the blood after administration of the antibody provides a simple straightforward diagnostic test for both clinical and preclinical Alzheimer's disease and related neurological disorders.
There are additional relevant publications concerning the behavior of Aβ peptide antibodies. For example, PCT publication WO99/27944 published 10 Jun. 1999 describes methods to induce an immune response in order to reduce amyloid deposits. Publication No. WO99/60024 published 25 Nov. 1999, describes methods for amyloid removal using anti-amyloid antibodies. Additional PCT publications, including WO00/72880, WO00/72876 and WO00/77178 all describe various activities of anti-Aβ peptide antibodies. Antibodies directed to the N-terminus of this peptide are said to reduce plaques in a transgenic murine model; immunization with the amyloid itself is described as are antibodies designed to catalyze hydrolysis of the peptide.
It has been shown that one pathway for Aβ metabolism is via transport from CNS to the plasma (Zlokovic, B. V., et al., Proc. Natl. Acad. Sci (USA) (1996) 93:4229-4234; Ghersi-Egea, J-F., et al., J. Neurochem. (1996)67:880-883). Additionally, it has been shown that Aβ in plasma can cross the blood-brain-barrier and enter the brain (Zlokovic, B. V., et al., Biochem. Biophys. Res. Comm. (1993) 67:1034-1040). It has also been shown that administration of certain polyclonal and monoclonal AO antibodies decreases Aβ deposition in amyloid plaques in the APPV717F transgenic mouse model of Alzheimer's disease (Bard, F., et al., Nature Med. (2000) 6:916-919). This was said to be due to certain anti-Aβ antibodies crossing the blood-brain-barrier and stimulating phagocytosis of amyloid plaques by microglial cells. In Bard's experiments, assays of brain slices ex vivo showed that the presence of added Aβ antibody, along with exogenously added microglia, induced phagocytosis of Aβ, resulting in removal of Aβ deposits.
The levels of both soluble Aβ40 and Aβ42 in CSF and blood can readily be detected using standardized assays using antibodies directed against epitopes along the Aβ chain. Such assays have been reported, for example, in U.S. Pat. Nos. 5,766,846; 5,837,672; and 5,593,846. These patents describe the production of murine monoclonal antibodies to the central domain of the AO peptide, and these were reported to have epitopes around and including positions 16 and 17. Antibodies directed against the N-terminal region were described as well. Several monoclonal antibodies were asserted to immunoreact with positions 13-28 of the Aβ peptide; these did not bind to a peptide representing positions 17-28, thus, according to the cited patents, establishing that it is this region, including positions 16-17 (the ⋄-secretase site) that was the target of these antibodies. Among antibodies known to bind between amino acids 13 and 28 of Aβ are mouse antibodies 266 (m266), 4G8, and 1C2.